In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. 10032-10032
Abstract:
10032^ Background: Panobinostat (LBH589; P) is a pan-deacetylase-inhibitor that has preclinical activity in combination with IM in GIST models in vitro and in vivo. Aim of this study was to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of escalating doses of P in combination with IM in patients with GIST who have failed IM and sunitinib treatment. Methods: This was a two-center phase I study using a 3+3 design with a prespecified expansion of the MTD cohort. IM was administered at a dose of 400mg qd. Following a 7 day run-in phase, escalating doses of P were added. The starting dose for P was 20 mg given as a three-times-per-week (MWF schedule) oral dose for 3 out of 4 weeks. Doses were increased by 10 mg if no dose limiting toxicities emerged. Blood samples were drawn for PK and biomarker assessments of IM, its main metabolite N-desmethyl-IM, and P using a validated RP-HPLC method. Acetylation of histone A3 was evaluated in peripheral blood mononuclear cells (PBMNC) as pharmacodynamic marker for P activity. Metabolic response using PET (EORTC-PET study criteria) was assessed on day 7 of IM run-in and after 3 weeks of combined treatment with IM and P. Results: In total 12 extensively pretreated (median 5 pretreatments) pts (4 f, 8 m; median age 56 y, 34-75 y) received study treatment at 2 dose levels (DL). 2 dose-limiting toxicities (grade 4 thrombocytopenia) occurred at DL 2 (30 mg). Most common AEs were thrombocytopenia, anemia, fatigue, nausea, emesis, diarrhea, creatinine elevation, abdominal cramping, and weight loss. DL 1 (20mg) was declared MTD, and 5 additional pts were enrolled at DL1. Analysis of P and IM PK revealed mean peak concentration of 14.8 +/- 9.5 ng/ml for P (20 mg). IM plasma concentrations with 400 mg once-daily administration were 2.8 ± 1.1 μg/mL at peak and 1.2 ± 0.4 μg/mL at trough. Histone A3 acetylation was demonstrated in PBMNC from pts treated at DL 1. 11 pts were evaluable for PET response: 1 had mPR, 7 had mSD and 3 had mPD. Longest treatment duration was 17 weeks (median: 6wks). Conclusions: P in combination with IM is moderately tolerated. Evidence of target inhibition at the MTD was associated with limited clinical activity in heavily pretreated pts with GIST.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/jco.2012.30.15_suppl.10032
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2012
detail.hit.zdb_id:
2005181-5
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